This project will utilize newly developed assays for a battery of oxidative DNA adducts to better define dose and time responses for oxidative stress induced by exposure to PCBs and TCDD using liver and lung samples from 13, 30 and 52-week tissues from Sprague-Dawley rats exposed to pentachlorodibenzofuran, PCB 118, or mixtures of TCDD, PeCDF and PCB 126 from the NTP Toxic Equivalency Factor (TEF) studies. These studies will demonstrate the relationships between endogenous DNA adducts and carcinogenesis and determine if the """"""""oxidative stress"""""""" Mode of Action for this important set of nongenotoxic chemicals is supported. Endogenous DNA adducts can be converted to mutations if DNA replication takes place before repair. Unlike DNA adducts, mutations cannot be repaired and are heritable in the progeny of the originally mutated cell. We have shown that endogenous DNA lesions are always present in genomic DNA, attaining >40,000 adducts per cell. Since most of these lesions are potentially mutagenic, this nonzero background of endogenous DNA damage is a likely cause of the nonzero spontaneous background mutation rate. We will develop new methods for studying mutations using the PIG gene in DT-40 cells and will employ this system to evaluate the dose-response for mutations resulting from chemicals that form DNA adducts identical to endogenously formed adducts in cells and tissues. This research will provide highly informative scientific data to be used in future cancer risk assessments, rather than relying on linear default science policy decisions that may not provide additional protection to public health, but pose expensive and often non-attainable clean-up levels for Superfund sites. Finally, we will collaborate with Projects 2, 3, 4 and 5 respectively, to determine the role of oxidative stress in the toxicity of trichloroethylene;identify critical DNA response pathways for cadmium;evaluate CAFLUX and CALUX cell biological responses to samples of environmental contaminants;and examine toxicity and DNA damage response pathways of original extracts and their fractionated and purified samples of PAH mixtures that have undergone bioremediation.

Public Health Relevance

This research will clarify the role of oxidative stress in the toxicity and carcinogenicity of TCDD and PCBs and demonstrate the role of endogenous DNA adducts in mutagenesis. Using these data, it will determine critical dose-response relationships necessary for science-based low dose extrapolation of cancer risk assessments.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Hazardous Substances Basic Research Grants Program (NIEHS) (P42)
Project #
5P42ES005948-20
Application #
8450231
Study Section
Special Emphasis Panel (ZES1-LWJ-V)
Project Start
Project End
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
20
Fiscal Year
2013
Total Cost
$380,589
Indirect Cost
$129,310
Name
University of North Carolina Chapel Hill
Department
Type
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Balik-Meisner, Michele; Truong, Lisa; Scholl, Elizabeth H et al. (2018) Elucidating Gene-by-Environment Interactions Associated with Differential Susceptibility to Chemical Exposure. Environ Health Perspect 126:067010
To, Kimberly T; Fry, Rebecca C; Reif, David M (2018) Characterizing the effects of missing data and evaluating imputation methods for chemical prioritization applications using ToxPi. BioData Min 11:10
Dalaijamts, Chimeddulam; Cichocki, Joseph A; Luo, Yu-Syuan et al. (2018) Incorporation of the glutathione conjugation pathway in an updated physiologically-based pharmacokinetic model for perchloroethylene in mice. Toxicol Appl Pharmacol 352:142-152
Gray, Kathleen M (2018) From Content Knowledge to Community Change: A Review of Representations of Environmental Health Literacy. Int J Environ Res Public Health 15:
Li, Gen; Jima, Dereje; Wright, Fred A et al. (2018) HT-eQTL: integrative expression quantitative trait loci analysis in a large number of human tissues. BMC Bioinformatics 19:95
Adebambo, Oluwadamilare A; Shea, Damian; Fry, Rebecca C (2018) Cadmium disrupts signaling of the hypoxia-inducible (HIF) and transforming growth factor (TGF-?) pathways in placental JEG-3 trophoblast cells via reactive oxygen species. Toxicol Appl Pharmacol 342:108-115
Smeester, Lisa; Fry, Rebecca C (2018) Long-Term Health Effects and Underlying Biological Mechanisms of Developmental Exposure to Arsenic. Curr Environ Health Rep 5:134-144
Luo, Yu-Syuan; Furuya, Shinji; Chiu, Weihsueh et al. (2018) Characterization of inter-tissue and inter-strain variability of TCE glutathione conjugation metabolites DCVG, DCVC, and NAcDCVC in the mouse. J Toxicol Environ Health A 81:37-52
Singleton, David R; Lee, Janice; Dickey, Allison N et al. (2018) Polyphasic characterization of four soil-derived phenanthrene-degrading Acidovorax strains and proposal of Acidovorax carolinensis sp. nov. Syst Appl Microbiol 41:460-472
Luo, Yu-Syuan; Hsieh, Nan-Hung; Soldatow, Valerie Y et al. (2018) Comparative analysis of metabolism of trichloroethylene and tetrachloroethylene among mouse tissues and strains. Toxicology 409:33-43

Showing the most recent 10 out of 505 publications